NM_018426.3:c.37G>C

Variant names:

• chr6-44134621-G-C
• rs1762568711
• NM_018426.3:c.37G>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_018426.3(TMEM63B):​c.37G>C​(p.Ala13Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000144 in 1,461,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: TMEM63B NM_018426.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.33
• Publications: 0 publications found

Genes affected

TMEM63B (HGNC:17735): (transmembrane protein 63B) Predicted to enable calcium activated cation channel activity; mechanosensitive ion channel activity; and osmolarity-sensing cation channel activity. Predicted to be involved in cation transmembrane transport. Located in actin cytoskeleton and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM63B Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• TMEM63B-related developmental and epileptic encephalopathy with anemia

  Inheritance: AD Classification: MODERATE Submitted by: G2P

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 4.2176 (above the threshold of 3.09). Trascript score misZ: 5.4805 (above the threshold of 3.09). GenCC associations: The gene is linked to TMEM63B-related developmental and epileptic encephalopathy with anemia, complex neurodevelopmental disorder.
• BP4: Computational evidence support a benign effect (MetaRNN=0.23994195).
• BS2: High AC in GnomAdExome4 at 21 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018426.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM63B	NM_018426.3	MANE Select	c.37G>C	p.Ala13Pro	missense	Exon 2 of 24	NP_060896.1	Q5T3F8-1
	TMEM63B	NM_001318792.1		c.37G>C	p.Ala13Pro	missense	Exon 2 of 24	NP_001305721.1	Q5T3F8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM63B	ENST00000323267.11	TSL:5 MANE Select	c.37G>C	p.Ala13Pro	missense	Exon 2 of 24	ENSP00000327154.6	Q5T3F8-1
	TMEM63B	ENST00000259746.13	TSL:2	c.37G>C	p.Ala13Pro	missense	Exon 2 of 24	ENSP00000259746.9	Q5T3F8-1
	TMEM63B	ENST00000872088.1		c.37G>C	p.Ala13Pro	missense	Exon 3 of 25	ENSP00000542147.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461774 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 727192

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111992

Other (OTH) AF: 0.0000497 AC: 3 AN: 60390

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000468 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.051
Eigen_PC	Benign	0.048
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PhyloP100		4.3
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.14
Sift	Benign	0.059	T
Sift4G	Benign	0.34	T
Polyphen		0.61	P
Vest4		0.47
MutPred		0.37		Gain of loop (P = 0.0097)
MVP		0.17
MPC		1.7
ClinPred		0.52	D
GERP RS		3.2
PromoterAI		0.0076	Neutral
Varity_R		0.11
gMVP		0.66
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1762568711; hg19: chr6-44102358;